This invention relates to the treatment of renal cell carcinoma.
Renal cell carcinoma can progressively develop into widespread metastatic disease. Originating on the surface of the renal cortex, the small, localized primary tumor rarely produces noticeable symptoms during the early stages of disease (e.g., Stages I and II). Early stage renal cell carcinoma is frequently identified incidentally through diagnostic readings performed in the evaluation of an unrelated condition (MRI scans, for example). As the disease progresses, symptoms can present as a classic triad consisting of hematuria, a palpable mass in the flank or abdomen, and pain. In Stages I-III, partial (e.g., Stage I) or total (Stages II and III) surgical removal of the kidney remains the only known effective therapy for localized renal cell carcinoma. Of course, if both kidneys are involved, surgery is usually not an option.
In 30% to 50% of patients, progression to metastatic disease (Stage IV) occurs prior to initial diagnosis. However, traditional therapeutic modalities, including chemotherapy and radiation, are largely ineffective in Stage IV patients. Immunotherapy using interleukin-2 (IL-2) or xcex1-interferon as first-line treatment is a viable option and has been proven to offer an objective response in some patients.
Nonetheless, almost all Stage IV patients are considered incurable. Tumor embolization, external-beam irradiation, and nephrectomy can aid in the palliation of symptoms due to the primary tumor or related ectopic hormone production. There is minimal evidence that nephrectomy induces regression of distant metastases. Thus, nephrectomy, in the hope that it will be followed by spontaneous regression of metastases, is invariably not advised. Spontaneous regressions rarely but occasionally occur. Indeed, a prospective surveillance series of 73 patients with advanced renal cell cancer demonstrated apparent temporary objective regression in 5 (7%) patients without nephrectomy or any therapy. Selected patients with solitary or a limited number of distant metastases can achieve prolonged survival with nephrectomy and surgical resection of the metastases. This has been shown to be the case even for patients with brain metastases. The likelihood of achieving therapeutic benefit with this approach appears enhanced in patients with a long disease-free interval between the initial nephrectomy and the development of metastatic disease.
Responses to cytotoxic chemotherapy generally do not exceed 10% for any regimen that has been studied in adequate numbers of patients. Because of early reports of success, progestational agents have been administered to patients with metastatic renal cell cancer, but the frequency of response is disappointingly low, and there is reportedly no rationale for their use as anticancer therapy. They may offer subjective palliation, however.
Various biologic therapies also have been evaluated. Interferon alfas have approximately a 15% objective response rate in appropriately selected individuals. In general, these patients have non-bulky pulmonary and/or soft tissue metastases with excellent performance status (ECOG 0,1) and no weight loss. The interferon-xcex1 doses used in studies reporting good response rates have been in an intermediate range, 6-20 MU-TIW. These responses are rarely complete or durable.
Somewhat more promising are interleukin-2 (xe2x80x9cIL-2xe2x80x9d) treatments. Administration of IL-2 appears to have a similar overall response rate to interferon-xcex1, but with approximately 5% of the appropriately selected patients having durable complete remissions. Combinations of IL-2 and interferon have been studied but reportedly have not been shown to be better than high-dose IL-2 alone. The optimum dose of IL-2 is not completely established. High-dose therapy appears to be associated with higher response rates but with more toxic effects. Low-dose inpatient regimens can reportedly retain efficacy with fewer toxic effects, especially hypotension. Outpatient, subcutaneous administration has also demonstrated responses with acceptable toxic effects. Because of the overall poor results with drug treatment, patients with metastatic renal cell cancer are recommended to be considered for clinical trials, especially phase I and II trials evaluating newer chemotherapeutic agents and biologics such as interferons or IL-2 and strategies to modulate multidrug-resistant phenotype, which is highly expressed in renal cell cancers.
Thus, there is a great need for new, effective therapies for the treatment of renal cell carcinoma.
This invention represents a novel therapy for treating renal cell carcinoma patients without the substantial side effects of prior pharmaceutical approaches. Specifically, this invention involves the administration of an inhibitor of phosphodiesterase 10 (xe2x80x9cPDE10xe2x80x9d). Such an inhibitor also advantageously inhibits PDE2 and PDE5.
We surprisingly found that PDE10 is present in renal cell carcinoma, and that its inhibition leads to death of such cells. We are unaware of any reports from prior investigators who claim to have located expressed PDE10 protein in human tissue. To date, investigators have typically located PDE10 message in selected human tissue with little, if any, protein.